Tuberculosis resulting from infection with Mycobacterium tuberculosis (Mtb) is a serious global health problem accounting for 1.4 million deaths in 2011. A major reason for the high morbidity and mortality caused by Mtb is the long duration of therapy and increasing multidrug-resistance of Mycobacterium strains.
Mtb has been treated with combination therapy for over fifty years. Anti-tuberculous first line oral drugs used in the treatment of Mtb are principally Ethambutol (EMB), Isoniazid (INH), Pyrazinamide (PZA), Rifampicin (RMP), Rifampin (RIP) and Rifabutin (RFB).
Reports of high rates of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) in recent years have highlighted the failure of Mtb therapy. According to the latest WHO statistics, approximately half a million new cases of MDR-TB are diagnosed every year. Of these, it is estimated that approximately 40,000 have extensively drug-resistant tuberculosis (XDR-TB).
MDR-TB is defined as resistance to at least Isoniazid and Rifampicin, the two most effective first-line antituberculous drugs. The treatment regimen for MDR-TB comprises a later generation fluoroquinolone (moxifloxacin, gatifloxacin, or levofloxacin), an injectable aminoglycosides (either amikacin, kanamycin), any first-line drug to which the isolate is susceptible, and the addition of drugs such as cycloserine/terizidone and ethionamide. XDR-TB, in addition to the resistance observed for MDR-TB, is defined by a resistance to any fluoroquinolone and any injectable second line aminoglycoside drug. Thus, the design of a treatment regimen for XDR-TB is more complex.
Importantly, these drugs are less effective, more expensive, more toxic and require longer course of treatment than drugs used in the treatment of susceptible organisms.
Therefore, there is a need for novel highly effective and specific compounds to combat Mtb, MDR-TB and XDR-TB with fewer adverse reactions.